Technetium-99m (Tc-99m) is the most commonly used radioisotope in nuclear medicine. Tc-99m is typically obtained as a daughter radionuclide from its parent isotope, molybdenum-99 (Mo-99), itself produced from the fission of uranium-235 in nuclear reactors. The Mo-99 is typically packaged in an alumina cartridge, to which it binds tightly, and Tc-99m pertechnetate is eluted from the alumina cartridge by using an isotonic sodium chloride solution. This device, called a generator, is optimally used with high specific activity Mo-99, due to the low binding capacity of the alumina cartridges. Low specific activity Mo-99 is obtained with alternative production methods such as neutron enrichment of Mo-98, or by the use of the photon-neutron process by a linear accelerator. In addition, during the manufacturing process of Tc-99m using medical cyclotrons using Mo-100, a large excess of the target material (Mo-100) remains with the Tc-99m after dissolution of the target material. The use of larger alumina cartridges leads to large elution volumes of Tc-99m, which limits its practical utility for clinical use.
Several authors have reported various methods to separate Tc-99m from low specific activity molybdenum. Zirconium molybdate gels have been used to immobilize molybdenum (Evans, 1987), and this type of generator is used in countries that rely on low specific activity Mo-99. Liquid extraction chromatography of Tc-99m with methyl ethyl ketone was also used to isolate Tc-99m, but this approach is less amenable to automation and can be technically challenging (Dash, 2012). The use of ion exchange separation chromatography to separate technetium from molybdenum has been known since the 1950s using Dowex resins for example, and several improvements to this approach have been reported over the years. Various authors have reported the use of sequential solid phase extraction cartridges to concentrate Tc-99m and reduce the volume of the eluates (Blower, 1993). A summary of various methods available for Tc-99m purification from Mo-99 was recently published on-line (Dash, 2012). Rogers et al. reported the use of aqueous biphasic chromatography (Rogers 1993-1997). The use of polyethylene/polypropylene glycols (PEG/PPG) covalently attached to polystyrene particles for the separation of Tc-99m is described in U.S. Pat. No. 5,603,834, which is hereby incorporated by reference, and is available commercially under the name ABEC (aqueous biphasic extraction chromatography).
Among the various methods available, the inventors have previously tested the use of strong anion exchange resins as well as ABEC resin to separate Tc-99m from low specific activity molybdenum (Morley, 2012). Both methods gave adequate results. The anion exchange method (using Dowex 1X8 resin) suffers from the disadvantage of using organic solvents and quaternary amines, which complicate the quality control of the final product. The ABEC resin provided better performance but led to some losses of Tc-99m due to incomplete trapping or elution of the Tc-99m. In addition, polystyrene resins are sensitive to heat, and their resistance to radiolysis is unknown.
It has been known for some years that PEG-linked polystyrene resins could improve the yields for solid-phase synthesis of some peptides. A cross-linked resin made wholly from polyethylene glycol, without attachment to a particle or polystyrene bead, has been developed for solid-phase peptide synthesis and is commercially available from PCAS Biomatrix Inc., under the name ‘ChemMatrix’® (Garcia-Martin 2006). This completely PEG based resin is sold with various functional groups for solid phase peptide synthesis. Compared to polystyrene-based resins, these resins have a high binding capacity, improved chemical resistance, and higher swelling in water.
There remains a need for improved procedures for purification and separation of Tc-99m salts from solutions of parent isotopes of molybdenum that are produced from lower activity sources, e.g. during cyclotron or linear accelerator (LINAC) bombardment of enriched molybdenum targets, or from neutron capture of natural or enriched Mo-98 in a nuclear reactor.